The disposition of amodiaquine in Zambians and Nigerians with malaria.

1. Oral amodiaquine (AQ) has been used to treat patients with symptomatic malaria in Zambia (n = 14) and Nigeria (n = 5). Clinical cure was obtained in all patients and no serious adverse drug reactions were seen. 2. As in healthy subjects, AQ achieved low plasma concentrations. Plasma concentration vs time profiles of desethylamodiaquine (AQm) from the present study did not differ from those obtained from healthy subjects. 3. In contrast to previous results from healthy subjects, the mean ratio of red cell (RBC): plasma AQm concentration in the present study was 0.80: 1 at the start of the study and rose in a linear manner (r = 0.873; P less than 0.01) to 3.04: 1 by the end (n = 10; P less than 0.01). The final mean value was similar to that seen in healthy subjects. 4. These data show that there are differences in the disposition of orally administered AQ between healthy subjects and patients with clinical malaria. The relevance of this observation to the frequency of adverse reactions to AQ in these two groups is not established.

Urinary excretion of mefloquine and some of its metabolites in African volunteers at steady state.

Because of the extremely long terminal elimination half-life of mefloquine it is practically impossible to measure quantitatively its urinary excretion after a single dose. Indeed, a correct estimation would require collection of urine over a period of several months. This difficulty was overcome by measuring excretion in the course of a multiple-dose study when steady-state conditions had been reached. Six male African volunteers were given at an interval of 1 week 250 mg mefloquine base in the form of its hydrochloride. Urine was quantitatively collected from each subject during the 11th week and analyzed for unchanged drug and its alcohol and acid metabolites. Excretion of the unchanged drug and of its acid metabolite amounted respectively to 9% (5.2-13.1%) and 4.2% (2.9-6.2%) of the weekly dose. Concentrations of the alcohol metabolite were too low to be measured.

A double-blind trial of a fixed combination of mefloquine plus sulfadoxine-pyrimethamine compared with sulfadoxine-pyrimethamine alone in symptomatic falciparum malaria.

A total of 100 male Zambian patients with symptomatic falciparum malaria were treated with either two tablets of mefloquine plus sulfadoxine-pyrimethamine (Fansimef) or three tablets of sulfadoxine-pyrimethamine (Fansidar) as a single dose. The patients were kept under observation from day 0 (day of treatment) to day 28 and all were cured. An S-type of response was seen in all patients; one patient in the Fansimef group inexplicably remained positive for Plasmodium falciparum trophozoites until day 6. There were no cases of recrudescence.The rate of clearance of parasitaemia was similar in both groups. The rate of clearance of fever was marginally faster in the Fansimef group. Side-effects such as pruritus, diarrhoea and abdominal pain occurred after both drugs but were mild and transient; tolerance was slightly better with Fansimef. Severe orthostatic hypotension occurred in 20% of the Fansidar patients and in only 2% of the Fansimef patients; this was reversed by bed rest. Haematological and biochemical parameters were generally not modified in an undesirable manner by the administration of these drugs.

A double-blind clinical trial of a combination of mefloquine, sulfadoxine and pyrimethamine in symptomatic falciparum malaria.

Fansimef is a combination of 250 mg of mefloquine, 500 mg of sulfadoxine, and 25 mg of pyrimethamine per tablet. A total of 150 adult male Zambian patients who had symptomatic Plasmodium falciparum parasitaemia were treated in a double-blind randomized fashion with either one, two or three tablets of Fansimef. All patients in the three treatment groups showed an S-type response. The rates of clearance of parasitaemia and fever were similar in all treatment groups. Tolerance was good at all dose levels. The main side-effects were abdominal discomfort, weakness and lassitude, dizziness, and pruritus, but these were mild, transient and required no specific treatment. Vomiting occurred only in 4% of patients given the highest dose of three tablets. The results of various haematological and biochemical investigations and urinalysis were not adversely altered by the administration of Fansimef.

A double-blind comparative clinical trial of mefloquine and chloroquine in symptomatic falciparum malaria.

A total of 99 male Zambian patients with symptomatic falciparum malaria were treated in a double-blind randomized manner with either mefloquine (1000 mg given in one day) or chloroquine (1500 mg given over 3 days). An S-type response was seen in all the chloroquine patients and 98% of the mefloquine group; one patient in the latter group (2%) showed an RI-type response, but the parasites obtained during the recrudescence were sensitive to both chloroquine and mefloquine in the in vitro microtest, and the patient responded satisfactorily to oral chloroquine. The rate of clearance of parasitaemia was marginally faster in the chloroquine-treated group. The rate of clearance of fever was similar in the two groups. Both drugs were well tolerated and side-effects such as nausea, vomiting, dizziness, loose stools, and pruritus were mild and transient. Pruritus was more common after chloroquine administration and dizziness more common in the mefloquine group. There were no drug-induced alterations in the haematological and biochemical profiles.

Management of clinical trials in developing countries.

PIP: Clinical trials need to consider specifics in trial circumstances when novel measures to improve health call for assessment in developing countries. Predictions regarding safety and efficacy under regional conditions, deriving from data of trials in affected populations in another part of the world, cannot always be accepted as reliable indicators of future regional performance. The primary objective should be to reveal new information. This discussion of the management of clinical trials in developing countries focuses on the following: the protocol; staff and supervision; locations and logistics; the use of a pilot study; drugs and compliance; and ethics. At an initial workshop a planning group with the broadest possible representation draws up a protocol. Ideally, the protocol is never imposed but is developed through extensive consultation and coordination. Its initial objective is an agreement on how to make a specific study feasible. Initial goals should be restricted to answering a few simple but meaningful questions. Information in the study protocol includes: aims and objectives; precise definitions of clinical variables; detailed description plus frequency and timing of clinical procedures, laboratory tests, and so forth; case report forms; consent forms and any warning notices written in the local language; work manuals for the pharmacist of drug supervisor; the treatment allocation procedure and individual treatment charts; the labeling code, emergency code breaking, and referral procedures; precise guidelines for evaluation and management of known adverse reactions; and an investigational data brochure. Selection of a competent, dependable, and enthusiastic principal investigator, available for the full duration of the study is essential. Suitable trial sites should be carefully chosen to avoid conditions that might prevent application of adequate scientific standards. In case of doubt about the logistical feasibility, starting with a trial run of the test procedures or with a pilot study using an established drug should be considered in order to detect potential problems concerning availability of scientific and technical expertise, equipment or reagents. It is necessary to check national clearances for investigating new agents. Permits may be required from a review body, a manufacturer, or from an authority. All needed drug supplies should be obtained at once together with information on stability under expected storage conditions. An independent measure of patient compliance needs to be agreed upon. Projects should be reviewed as well as approved by an independent local group, practicing the highest standards of protection of the rights of the individual. Data collection begins with identification of subjects, by photographs of faces, in addition to careful records of name, household, domicile, and occupation.^ieng

Single dose kinetics of mefloquine in man. Plasma levels of the unchanged drug and of one of its metabolites.

Oral single dose kinetics of mefloquine was investigated in 16 male volunteers, 3 Caucasians and 13 African natives. Unchanged mefloquine (= M) and one of its metabolites (= MM) were measured in the plasma. The apparent half-life of absorption of M ranged from 0.36 to 2.0 h, its terminal half-life of elimination from 15 to 33 days. Assuming complete systemic availability, an apparent volume of distribution of 14-29 liters x kg-1 and a total clearance of 18-39 ml x min-1 were derived. MM given orally to mice or rats showed at equal dose the same tolerance as mefloquine. Following oral administration of M to man, plasma levels of MM surpassed those of M, resulting in a 2.4-5.1 larger AUC. However, because of its much smaller apparent volume of distribution, MM may be anticipated to represent only a small percentage of the dose and therefore to contribute only to a minor extent towards the unwanted side effects of the drug.

Effect on neuromuscular transmission of repeated administration of an organophosphorus compound, metrifonate, during treatment of children with urinary schistosomiasis.

Muscle action potential amplitude recorded from abductor pollicis brevis in response to nerve stimulation was measured in 55 children during treatment of urinary schistosomiasis with metrifonate (3 doses at 2 weekly intervals). Mean erythrocyte cholinesterase activity was 52-75% of pretreatment value in different groups when examined electrophysiologically. Twenty-six children acted as controls. There was no difference in amplitude between control and exposed subjects 2 weeks after the 2nd dose. Six hours after the 3rd dose, amplitude was larger in some subjects. This effect was not related to dose or degree of cholinesterase inhibition and was thought unlikely to be the result of treatment. Three children who received the highest dose of metrifonate had developed repetitive activity 6 hr later. The criteria for its identification are described.

Observations on the effect of ß-adrenoceptor blocking drugs on glyceryl trinitrate tachycardia.

1 The administration of 0.5 mg glyceryl trinitrate by chewing and keeping under the tongue increased heart rate in normal subjects in the supine and erect posture. 2 There was no significant difference between the responses in the same subject on repeated administration of glyceryl trinitrate on different days but there was a significant difference between the responses in different subjects. 3 The oral administration of practolol and propranolol reduced the responses to glyceryl trinitrate. The two drugs progressively reduced the increase in heart rate produced by glyceryl trinitrate; there was no significant difference between their effects. Propranolol produced a significantly greater reduction than practolol in the maximum heart rate that was produced by glyceryl trinitrate. 4 The administration of practolol (300 mg) twice daily by mouth to patients after an acute episode of ischaemic heart disease significantly reduced the increases in heart rate produced by standing and by glyceryl trinitrate in comparison to the responses in similar patients receiving a placebo.